Maytansinoids are highly cytotoxic drugs. The first member of this class, maytansine, was isolated by Kupchan et al. from the east African shrub Maytenus serrata and shown to be 100 to 1000 fold more cytotoxic than conventional cancer chemotherapeutic agents like methotrexate, daunorubicin, and vincristine (U.S. Pat. No. 3,896,111). Subsequently, it was discovered that some microbes also produce maytansinoids, such as maytansinol and C-3 esters of maytansinol (U.S. Pat. No. 4,151,042). Synthetic C-3 esters of maytansinol and analogues of maytansinol have also been reported (Kupchan et al. J. Med. Chem. 21:31-37 (1978); Higashide et al. Nature 270:721-722 (1977); Kawai et al. Chem. Pharm. Bull. 32:3441-3451 (1984)). Examples of analogues of maytansinol from which C-3 esters have been prepared include maytansinol with modifications on the aromatic ring (e.g. dechloro) or at the C-9, C-14 (e.g. hydroxylated methyl group), C-15, C-18, C-20 and C-4,5.
The naturally occurring and synthetic C-3 esters of maytansinol can be classified into two groups:    (a) Maytansine and its analogs described above, which are C-3 esters with N-methyl-L-alanine or derivatives of N-methyl-L-alanine (U.S. Pat. Nos. 4,137,230; 4,260,608; 5,208,020; and Chem. Pharm. Bull. 12:3441 (1984)); and    (b) Ansamitocins, which are C-3 esters with simple carboxylic acids (U.S. Pat. Nos. 4,248,870; 4,265,814; 4,308,268; 4,308,269; 4,309,428; 4,317,821; 4,322,348; and 4,331,598).
Ansamitocins are a mixture of compounds composed predominantly of ansamitocin P-2, ansamitocin P-3, ansamitocin P-3′, ansamitocin P-4 and ansamitocin P-4′, FIG. 1. The ansamitocin P-3 component of ansamitocins typically comprises over 70% of the total material in ansamitocins. Thus the mixture is often referred to as ansamitocin P-3. Ansamitocins are prepared by bacterial fermentation as described in U.S. Pat. Nos. 4,162,940, 4,356,265, 4,228,239, and 6,790,954.
Maytansine, its analogs, and each of the ansamitocin species are C3-esters of maytansinol that can be converted to maytansinol by cleavage of their respective ester side chains. Structures of maytansinols and several C3 esters are shown in FIG. 1. Typically, cleavage of the ester moiety is achieved through a reduction reaction. Thus, for example, C3-esters of maytansinol can be cleaved by treatment with lithium tri-methoxyaluminum hydride (LATH) or by other alkali alkoxyaluminum hydrides at reduced temperatures, followed by quenching with water or an aqueous salt solution and extraction with organic solvent to give maytansinol, as described in U.S. Pat. No. 6,333,410. Maytansinol is the common starting material for the preparation of various maytansinoid drugs, as described in U.S. Pat. Nos. 4,322,348, 4,331,598 and 6,333,410. The processes of preparing maytansinol described thus far are tedious to perform and are time consuming, because the aluminum-based byproducts of the reduction can form suspensions or gels that are difficult to extract and that can retain significant amounts of product. Anderson, N. “Practical Process Research & Development” (2000) ISBN # 0-12-059475-7 pages 72.